Genome-scale DNA methylation maps of pluripotent and differentiated cells.

Nature
Authors
Keywords
Abstract

DNA methylation is essential for normal development and has been implicated in many pathologies including cancer. Our knowledge about the genome-wide distribution of DNA methylation, how it changes during cellular differentiation and how it relates to histone methylation and other chromatin modifications in mammals remains limited. Here we report the generation and analysis of genome-scale DNA methylation profiles at nucleotide resolution in mammalian cells. Using high-throughput reduced representation bisulphite sequencing and single-molecule-based sequencing, we generated DNA methylation maps covering most CpG islands, and a representative sampling of conserved non-coding elements, transposons and other genomic features, for mouse embryonic stem cells, embryonic-stem-cell-derived and primary neural cells, and eight other primary tissues. Several key findings emerge from the data. First, DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Second, methylation of CpGs are dynamic epigenetic marks that undergo extensive changes during cellular differentiation, particularly in regulatory regions outside of core promoters. Third, analysis of embryonic-stem-cell-derived and primary cells reveals that 'weak' CpG islands associated with a specific set of developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, in a pattern reminiscent of that reported in some primary tumours. More generally, the results establish reduced representation bisulphite sequencing as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine.

Year of Publication
2008
Journal
Nature
Volume
454
Issue
7205
Pages
766-70
Date Published
2008 Aug 07
ISSN
1476-4687
URL
DOI
10.1038/nature07107
PubMed ID
18600261
PubMed Central ID
PMC2896277
Links
Grant list
R01 HG004401 / HG / NHGRI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
U54 HG003067-04 / HG / NHGRI NIH HHS / United States
U54 HG003067-06 / HG / NHGRI NIH HHS / United States
R01 HG004401-02 / HG / NHGRI NIH HHS / United States